Acute renal failure (ARF) is associated with a 40% mortality rate in the ICU, while acute lung injury (ALl) is associated with a 35% mortality. ARF and ALl frequently co-exist, and when this occurs, the mortality rate is 80%. Despite this frustrating outcome, little is known about the relationships between ARF and VALI. Recent studies from our team demonstrate that ARF directly contributes to lung dysfunction. We have found that lungs in experimental ARF had a marked increase in microvascular inflammation, pulmonary vascular permeability, and dysregulation of transporters implicated in lung edema clearance. In turn, it has been known for many years that mechanical ventilation can independently lead to changes in renal function. Preliminary data from our group has demonstrated that injurious mechanical ventilation may influence the systemic inflammatory response by leading to upregulation of intra-renal cytokines and adhesion molecules, which are putative mediators in the development of ARF. Based on these data, we hypothesize that ARF predisposes to VALI, and that in turn, VALI predisposes to ARF. We hypothesize that high volume ventilation directly contributes to the systemic inflammatory response manifest in the kidneys, and that inflammatory pathways mediated by leukocytes and leukocyte adhesion molecules are important mechanisms underlying the links between VALI and ARF. We will test these hypotheses using established murine models of ARF and ALl. Aim 1. Determine the effects of ARF on the lung: histology, function, inflammation, expression of fluid and electrolyte transporters, and gene expression. Aim 2. Test the hypothesis that ARF predisposes the lung to the injurious effects of high tidal volumes and hydrochloric acid. Aim 3. Evaluate the effects of VALI on the kidney. Kidney histology, function, inflammation, and fluid and electrolyte transporters will be assessed. For each of these three aims, we will test the hypothesis that the lung-kidney links are mediated by leukocyte adhesion molecules, and intervene in the CD18-1CAM-1 and selectin pathway. Genomic and proteomic techniques will be used to generate mechanistic hypotheses about pathways mediating ARF/VALI interactions. Close cooperation with histology and biomarker cores will be performed to measure endpoints. The canine core will delineate the hemodynamic and biomechanical aspects of mechanical ventilation effects on kidney. Collaboration on renal outcomes will be undertaken with Project 4 examining endothelial integrity and interventions, and Project 6 regarding effects of hyperoxia. The proposed studies will lead to a better understanding of ARF/VALI interactions and hopefully lead to new therapies.